Significance of Persistent Inflammation in Patients With Chronic Coronary Syndrome

Background The prognostic implications of persistent low-grade inflammation in patients with chronic coronary syndrome (CCS) are underexplored. The REAL-CAD (Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease) study demonstrated the benefit of higher intensity pitavastatin in Japanese patients with CCS. Objectives This prespecified subanalysis of the REAL-CAD study aimed to assess the prognostic effect of the persistent low-grade inflammation represented by high-sensitivity C-reactive protein (hs-CRP) in CCS patients. Methods The present analysis involved patients without events until 6 months after randomization and whose hs-CRP levels were available at baseline and 6 months (n = 10,460). The primary endpoint was the composite of cardiovascular mortality, myocardial infarction, stroke, and unstable angina hospitalization. Landmark analyses evaluated the prognostic impact of continuous inflammation in 4 groups based on the median levels of hs-CRP (0.5 mg/L for both) at baseline and 6 months. The 4 groups included patient with persistently low, elevated (increased), reduced, and persistently high hs-CRP. Results Adjusted Cox proportional hazard analyses demonstrated an increased risk of the primary endpoint in the group with persistently high hs-CRP when compared to the group with persistently low hs-CRP as a reference (adjusted HR: 1.48, 95% CI: 1.18-1.89; P = 0.001), but with a similar risk in the group with elevated (HR: 1.07, 95% CI: 0.77-1.49, P = 0.68) and reduced (HR: 0.92; 95% CI: 0.66-1.27; P = 0.60) hs-CRP. Conclusions The study shows that persistent low-grade inflammation is associated with poor outcomes and underscores the need to address residual inflammatory risk in CCS patients. (Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy With Pitavastatin in Coronary Artery Disease [REAL-CAD]; NCT01042730)

L owering of low-density lipoprotein cholesterol (LDL-C) by statins is a firmly established anti-atherosclerotic intervention and is associated with a reduced risk of adverse cardiovascular (CV) events in patients with atherosclerotic CV disease, particularly those with coronary artery disease (CAD). 1,2Previous randomized trials and their metanalyses of intensive vs lessintensive statins have consistently demonstrated a favorable prognostic impact of a more intensive strategy. 3,4Studies of nonstatin LDL-C lowering interventions, including ezetimibe and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, have also showed a significant reduction in the risk of adverse CV events, when they are concomitantly used on the top of statins. 5,6Accordingly, recent guidelines strongly recommend an intensive LDL-C lowering strategy in highrisk patients, particularly in secondary prevention in patients with a history of atherosclerotic CV disease. 7,8wever, although these aggressive LDL-C lowering strategies strengthen the notion of "the lower, the better," there is still intense debate as to whether the positive impact of one or combinations of these LDL-C lowering strategies can be universally explained only by the LDL-C lowering effect. 9evious basic and clinical studies have indicated that statins possess a suppressive effect against vascular inflammation, which is considered to be at the center of the pathophysiology of atherosclerosis, 10 and such an anti-inflammatory effect by statins has been suggested to be independent of LDL-C lowering properties. 11[14] The REAL-CAD (Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease) study demonstrated the prognostic superiority of 4 mg/d pitavastatin compared to 1 mg/d in Japanese patients with CCS. 15 This prespecified subanalysis of the REAL-CAD study aimed to assess the prognostic impact of continuous low-grade inflammation and its possible therapeutic implications.

PARTICIPANTS AND METHODS
STUDY PARTICIPANTS AND DEFINED OUTCOME MEASURES.REAL-CAD was a prospective randomized open-label trial that enrolled 12,413 patients aged 20 to 80 years old with stable CAD, CCS, and a history of coronary revascularization, including percutaneous coronary intervention and coronary artery bypass graft surgery, or had angiographically proven significant stenosis (>75%) in a coronary artery. 16The hypothesis that higher-dose (4 mg/d) as compared  The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate.For more information, visit the Author Center.

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All reported P values are 2-sided.

BASELINE CHARACTERISTICS OF PATIENTS STRATIFIED BY SERUM LEVELS OF HS-CRP AT BASELINE AND
6-MONTH FOLLOW-UP.Patients in the persistently high hs-CRP group (Group D) were the oldest, while those in the persistently low hs-CRP group (Group A)   were the youngest and those in the other 2 groups were in between (Table 1).Patients in the persistently high hs-CRP group (Group D) were more likely to have comorbidities, including hypertension, AF, CKD, and history of heart failure and stroke.The proportion of patients taking beta-blockers and angiotensinconverting enzyme inhibitors/angiotensin receptor blockers was the highest in the persistently high hs-CRP group (Group D) and the lowest in the persistently low hs-CRP group (Group A).The ratios allocated to 4 mg/d of pitavastatin were lower in the groups of high hs-CRP at 6-month follow-up (Group C and D).Collectively, patients in the persistently high hs-CRP group (Group D) had a complex background with more comorbidities, as well as higher intensity medications.Such tendencies and differences were further enhanced when they were compared to those in the persistently low hs-CRP group (Group A).
Moreover, baseline and 6-month follow-up levels of hs-CRP were highest in the persistently high hs-CRP group (Group D) and lowest in the persistently low hs-CRP group (Group A).Baseline hs-CRP levels in the reduced hs-CRP group and that of 6-month follow-up in the elevated hs-CRP group were comparable and they had a slightly lower hs-CRP levels compared to persistently high hs-CRP group (Table 2).
Lipid parameters at multiple time points according to groups are listed and compared in Table 2.In the persistently high hs-CRP group (Group D), the levels of serum LDL-C and triglycerides were also constantly higher, and HDL-C was lower than those in patients with reduced and persistently low hs-CRP (Group A and B), partially due to the lower proportion of those assigned to 4 mg/d pitavastatin.However, P values in these comparisons are needed to be interpreted with caution, as they are not adjusted for multiple comparisons.
The level of hs-CRP at 6-month follow-up was significantly lower in patients allocated to 4 mg/d pitavastatin than in those allocated to 1 mg/d pitavastatin, although they were similar at baseline (Figure 1A).Moreover, by randomized allocations, the proportion in the persistently high hs-CRP group (Group D) was significantly lower in those allocated to 4 mg/d (34.5%) than in those allocated to 1 mg/d pitavastatin (38.4%).In contrast, that of the persistently low hs-CRP group (Group A) was higher in patients with 4 mg/d compared to 1 mg/d pitavastatin (38.9% vs 36.1%,respectively) (P < 0.001) (Figure 1B).remained highly significant for both the primary and secondary outcome measures, while there was no excess risk of the reduced and elevated hs-CRP groups (Group B and C) relative to the persistently low hs-CRP group (Group A) for the primary and secondary outcome measures (Figure 3A and B).
To assess the effect of inflammation in patients with and without achieving LDL-C goals in guidelinedirected lipid-lowering therapy (<70 mg/dL) 7,8,20 irrespective of randomized allocation, landmark Kaplan-Meier analyses stratified by the level of

DISCUSSION
OUTCOMES.The results of this prespecified subanalysis of the REAL-CAD study indicated a significant association between the presence of persistent inflammation and poor outcomes.Importantly, such a negative prognostic impact due to persistent inflammation was independent from baseline and achieved levels of LDL-C by pitavastatin (Central Illustration).
To reduce the risk of atherosclerotic CV disease, particularly in secondary prevention for patients with coronary, cerebrovascular, and peripheral atherosclerotic diseases, the current guidelines recommend intensive LDL-C lowering strategies using a combination of statins with ezetimibe or PCSK9 inhibitors. 7,8Particularly, previous intensive versus less-intensive statin outcome trials including REAL-CAD have suggested significant superiority for higher intensity statin therapy for reducing the risk of CV events as compared with less-intensive statin therapy. 3,4,15urthermore, non-statin LDL-C lowering medications in conjugation with statins, ezetimibe and PCSK9 inhibitors have also been shown to have benefits for further reduction in CV event risk compared to statins alone. 5,6However, despite the significant reduction in LDL-C levels by the combination of statins and non-statin medications, a substantial number of patients are still at risk for adverse CV events. 5,6Moreover, the prognostic benefit by LDL-C lowering medications was not completely parallel to the extent of LDL-C lowering.Indeed, a meta-analysis demonstrated that the risk reduction was more prone by increasing the intensity of statins compared to the addition of ezetimibe and PSCK-9 inhibitors, when it was adjusted by the extent of LDL-C reduction. 9[23] Chronic vascular inflammation plays crucial roles in the pathogenesis of atherosclerosis, which is regarded as a complex pathological process.Previous observational studies have indicated a significant pathological link between chronic inflammation and poor CV outcomes. 16This subanalysis of the REAL-CAD study has demonstrated a significant association between the presence of persistent inflammation and adverse CV outcomes in patients with CCS who were treated by low or moderate intensity pitavastatin, independent from known risk factors, particularly LDL-C levels, for patients with CCS.In the previous studies that evaluated the effects of treatments targeting inflammation on outcomes of atherosclerotic CAD, the medians of baseline hs-CRP levels were at least 2 mg/L, 4,[11][12][13][14] which were more than 4 times higher than in the present study.Therefore, the present study provides novel evidence that the residual inflammatory risk is significant even in a population whose inflammatory Adjusted risks of persistently high hs-CRP for primary endpoint (A) and cardiovascular mortality (B).1][32] Moreover, previous experimental and clinical studies have also indicated that ezetimibe has a similar anti-inflammatory effect. 33,34In this study, the proportion of persistently high hs-CRP was significantly lower, while that of persistently low hs-CRP was higher in patients who were allocated to    KEY WORDS Asians, coronary artery disease, inflammation, outcome, residual risk APPENDIX For supplemental figures and a table, please see the online version of this paper.

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with lower-dose (1 mg/d) pitavastatin therapy could reduce CV events was tested in the REAL-CAD study and patients were randomly assigned in a 1:1 ratio to treatment with 4 mg/d or 1 mg/d pitavastatin following a run-in period for at least 1 month.The baseline and follow-up high-sensitivity C-reactive protein (hs-CRP) levels were measured at randomization and at approximately 6 months (184.7 AE 42.1 days) later (6 months follow up hs-CRP).Similar to lipid parameters, such as LDL-C, highdensity lipoprotein-cholesterol (HDL-C), and triglycerides, serum was collected and hs-CRP level was centrally measured using a latex-enhanced nephelometry assay (Behring Nephelometer II, Siemens Healthcare Diagnostics Ltd).17

For
the present subanalysis of the REAL-CAD study, we excluded patients in whom either baseline or follow-up hs-CRP data were not available, and those who had the occurrence of the primary endpoint event before the follow-up hs-CRP measurement (n ¼ 1,953).In the eligible patients for the present analysis (n ¼ 10,460: 84.2% out of the total final analysis set of the REAL-CAD study population), the median levels of baseline and 6-month follow-up hs-CRP were 0.51 mg/L and 0.48 mg/L, respectively.Accordingly, participants in the present analysis were divided into 4 groups based on the cutoff level of hs-CRP (0.5 mg/L) at both baseline and 6-month follow-up; a persistently low hs-CRP group (Group A) (hs-CRP <0.5 mg/L both at baseline and at A B B R E V I A T I O N S A N D A C R O N Y M S AF = atrial fibrillation CAD = coronary artery disease CCS

2 0 2 4
Continuous Low-Grade Inflammation: A Residual Risk of Chronic Coronary Syndrome follow-up, n ¼ 3,914), reduced hs-CRP group (Group B) (hs-CRP $ 0.5 mg/L at baseline and <0.5 mg/L at 6-month follow-up, n ¼ 1,484), elevated hs-CRP group (Group C) (<0.5 mg/L at baseline and $0.5 mg/L at 6-month follow-up, n ¼ 1,282), and persistently high hs-CRP group (Group D) ($0.5 mg/L both at baseline and at 6-month follow-up, n ¼ 3,820) (Supplemental Figure1 CLINICAL OUTCOMES.Median follow-up durations in this study were 3.3 and 3.5 years after 6-month follow-up for the primary and secondary outcome measures, respectively.Landmark unadjustedKaplan-Meier analysis since follow-up hs-CRP measurement at 6 months demonstrated a significantly higher cumulative incidence of the primary outcome measure in the group with persistently high hs-CRP (Group D), compared to other 3 (Figure2A).Similarly, the cumulative incidence of CV death, which is the secondary outcome measure of the present study, was substantially higher in the persistently high hs-CRP group (Group D) than in other 3 groups (Group A to C) (Figure2B).In these 3 groups, the cumulative incidences of the primary and secondary outcome measures were similar.Even after adjusting for the confounders, including sex, age, current smoker, body mass index, diabetes, AF, CKD, and serum levels of lipid parameters at 6-month follow-up, LDL-C, HDL-C, and triglycerides, the excess risk of the persistently high hs-CRP group (Group D) relative to the persistently low hs-CRP group (Group A)

FIGURE 1
FIGURE 1 Temporal Changes in LDL-C and hs-CRP, and Distributions of 4 Groups Defined by hs-CRP Change From Baseline to 6 Months in Pitavastatin 1 mg/d vs 4 mg/d Groups ).

FIGURE 2 6
FIGURE 2 Landmark Analysis Starting From 6 Months After Randomization in Patients Stratified by Change of hs-CRP

FIGURE 3
FIGURE 3 Adjusted Risks of Persistently High hs-CRP for Outcomes

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A C C : A D V A N C E S , V O L . 3 , N O .7 Continuous Low-Grade Inflammation: A Residual Risk of Chronic Coronary Syndrome level was substantially lower than in the previous studies.Moreover, these findings are consistent with the previous cohort studies indicating a possible diversity in the levels of inflammation and hs-CRP by race and ethnicity. 26-28A recent health care-based Swedish study of patients after myocardial infarction showed that elevated hs-CRP >2 mg/L was seen in more than 60%, and indicated linear associations between levels of hs-CRP and CV risks, when they were within 2 to 5 mg/L, and that association was not shown in <1 mg/L. 29Therefore, the prognostic impact of hs-CRP <1 mg/L has not been clarified.A number of basic and preclinical studies have explored the anti-inflammatory effects of statins, ezetimibe, and PSCK9 inhibitors other than their LDL-C lowering properties.Statins, in particular, have

FIGURE 4
FIGURE 4 Prognostic Impact of hs-CRP at 6 Months in Patients With and Without Controlled LDL-C (<70 and $70 mg/dL) pitavastatin 4 mg/d compared to 1 mg/d, indicating the enhanced potency of the anti-inflammatory property of a higher dose of pitavastatin.These results were in line with the findings of the previous statin trials, whereby more intensive statin therapy was associated with reduced hs-CRP.3,4,[12][13][14]35  Thcombination of statin and ezetimibe yielded similar results, 36 while trials of PCSK9 inhibitors and their metanalysis have not shown a substantial impact on hs-CRP despite their potent LDL-C lowering property.22,36,37Moreover, consistent with previous investigations, no correlation was observed in the extent of LDL-C and hs-CRP lowering in the entire participant population of the REAL-CAD study and those assigned to receive 1 mg/d and 4 mg/d pitavastatin.These results indicate that the mechanisms of LDL-C lowering and anti-inflammatory property of pitavastatin are not dependent each other.STUDY LIMITATIONS.Several limitations of the present study should be considered.First, when evaluating the outcomes by hs-CRP level at randomization CENTRAL ILLUSTRATION Landmark Analysis of Patients With Chronic Coronary Syndrome Treated With Pitavastatin by Levels of High-Sensitivity C-Reactive Protein at Baseline and 6 Months: Subanalysis of the REAL-CAD Study Iwata H, et al.JACC Adv.2024;3(7):100996.hs-CRP ¼ high-sensitivity C-reactive protein; CCS ¼ chronic coronary syndrome.J A C C : A D V A N C E S , V O L . 3 , N O .7 Continuous Low-Grade Inflammation: A Residual Risk of Chronic Coronary Syndrome and 6 months later, the patient groups were not randomized.Therefore, the results of this study need to be interpreted with caution because they might have been influenced by unknown confounding factors and they do not necessarily indicate a causal relationship, although the prognostic impact was adjusted by multiple covariates.Furthermore, given the significant differences in the incidence of comorbidities among the groups, there is a potential risk of statistical bias due to inadequacy in the adjustment by the multivariate model.Second, due to the very low levels of hs-CRP in the REAL-CAD study population, it was difficult to assess the impact of the temporal change in hs-CRP (absolute difference or the ratio between baseline and 6-month follow-up).Third, the lack of data on additional inflammatory markers other than hs-CRP, such as interleukin-6, tumor necrosis factor-alpha, and molecules in transforming growth factor beta signaling might be a limitation of this study.The absence of these markers may restrict a comprehensive understanding of the inflammatory profile in this study population.Furthermore, as magnetic resonance imaging could provide insights into macrolesions, 38 future studies incorporating magnetic resonance imaging may provide a more comprehensive assessment of the inflammatory burden in patients with CCS.Despite these shortcomings, the present findings in the subanalysis of the REAL-CAD study have further strengthen the inflammation hypothesis in atherosclerosis by evaluating the prognostic impact of the continuous inflammation in CCS patients based on rigorous measurement of hs-CRP at 2 time points with a 6-month interval.Furthermore, the findings in this study indicate that persistent inflammation is an important therapeutic target when attempting to reduce the residual risk of atherosclerotic CV disease.CONCLUSIONS The present subanalysis of the REAL-CAD study indicate that persistent inflammation is substantially associated with poor outcomes even in Japanese CCS patients taking pitavastatin, although the levels of hs-CRP in this population are relatively low.Present findings may emphasize the need for a comprehensive approach that considers both achieved LDL-C levels and residual inflammatory risk in order to optimize patient management.ACKNOWLEDGMENTS The authors thank all patients and investigators who participated in REAL-CAD study; Yoji Mitadera and other members of the Public Health Research Foundation for their assistance as the administrative office; Teikyo Academic Research Center for its function as a data center.

31.
Jougasaki M, Ichiki T, Takenoshita Y, Setoguchi M. Statins suppress interleukin-6-PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: Critical roles of residual inflammation risk in atherosclerotic CV disease are gathering renewed attention.However, prognostic implications of low-grade inflammation in patients with CCS remain underexplored.In the REALCAD study, Japanese CCS patients exhibited lower inflammation levels than in previous studies.TRANSLATIONAL OUTLOOK: This subanalysis of the REAL-CAD study showed the adverse prognostic impact of low-grade persistent inflammation (hs-CRP >0.5 mg/l).These findings underscore the need for comprehensive approaches considering residual inflammatory risk in CCS patients.

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TABLE 2
Temporal Changes in hs-CRP and Lipid Parameters in the 4 Groups Values are median (IQR) or mean AE SD.HDL-C ¼ high-density lipoprotein cholesterol; hs-CRP ¼ high-sensitivity C-reactive protein; LDL-C ¼ low-density lipoprotein cholesterol.